Nuclear Localization of Heme Oxygenase-1 in Pathophysiological Conditions: Does It Explain the Dual Role in Cancer?

Abstract

Heme Oxygenase-1 (HO-1) is a type II detoxifying enzyme that catalyzes the rate-limiting step in heme degradation leading to the formation of equimolar quantities of carbon monoxide (CO), free iron and biliverdin. HO-1 was originally shown to localize at the smooth endoplasmic reticulum membrane (sER), although increasing evidence demonstrates that the protein translocates to other subcellular compartments including the nucleus. The nuclear translocation occurs after proteolytic cleavage by proteases including signal peptide peptidase and some cysteine proteases. In addition, nuclear translocation has been demonstrated to be involved in several cellular processes leading to cancer progression, including induction of resistance to therapy and enhanced metastatic activity. In this review, we focus on nuclear HO-1 implication in pathophysiological conditions with special emphasis on malignant processes. We provide a brief background on the current understanding of the mechanisms underlying how HO-1 leaves the sER membrane and migrates to the nucleus, the circumstances under which it does so and, maybe the most important and unknown aspect, what the function of HO-1 in the nucleus is.

Keywords: cancer; heme oxygenase-1; nuclear localization; nuclear protein; nucleus; oxidative stress.

Figure 1

(A) Critical regions for proteolytic cleavage by SPP and cysteine proteases, and for proteasome degradation, as well as the TMS and the predicted nucleocytoplasmic shuttling (NES and NLS) sequences are indicated in the amino acid sequence for HO-1 protein. (B) Regions for predicted nucleocytoplasmic shuttling (NES and NLS) sequences and the heme-binding site are indicated in 3D models of HO-1 protein.

Figure 2

Subcellular compartmentalization of HO-1 conditions its role in malignancies. Full-length HO-1 resides in the sER, is enzymatically active and may play an antitumor or protumor role. Truncated HO-1 resides in the nucleus, lacks enzymatic activity and may play a protumor role.

Figure 3

Mechanism of action of nuclear HO-1. Enzymatically active HO-1 is proteolitically cleaved from the sER and the generated t-HO-1 form migrates to the nucleus. Nuclear import of t-HO-1 is probably carried out by interaction with an importin, whereas nuclear export is carried out by interaction with CRM-1. Inside the nucleus, t-HO-1 may be acetylated by p300/CBP, binds to transcription factor as Nrf2 and AP-1 and activate them in order to transcribe genes related with antioxidant defenses and cell proliferation, among others.